This invention relates to an improved treatment for cancer comprising administering a combination of at least one camptothecin derivative and at least one other colorectal anticancer drug. More specifically, the invention relates to treatments for colorectal cancer comprising administering a synergistic therapeutically effective combination of Campto(copyright) (CPT-11, Irinotecan), 5-fluorouracil (5-FU), and folinic acid (FA).
Colorectal cancer is a leading cause of morbidity and mortality with about 300,000 new cases and 200,000 deaths in Europe and the U.S.A each year [Boyle P., Some recent developments in the epidemiology of colorectal cancer In: Bleiberg H., Rougier P., Wilke H. J., eds; Management of colorectal cancer London: Martin Dunitz: 19-34 (1998) and Midgley R. S., Kerr D. J., Systemic adjuvant chemotherapy for colorectal cancer In: Bleiberg H., Rougier P., Wilke H. J., eds.; Management of colorectal cancer: London: Martin Dunitz, 126-137 (1998)]. Although about fifty percent of patients are cured by surgery alone, the other half will eventually die due to metastatic disease, which includes approximately 25% of patients who have evidence of metastases at time of diagnosis.
In the United States, there are currently about 130,000 patients with colorectal cancer, 95,000 with colon cancer and 35,000 with rectal cancer. [American Cancer Society. Cancer Facts and FIGURES 2000.] Of these patients, 20% have metastatic disease at presentation, 40% will ultimately develop metastases, and 57,000 patients will die due to metastatic disease. [Id.].
5-FU has been the mainstay of chemotherapy for colorectal cancer for four decades. It has been shown to improve both survival time (11 months versus 5 months) and quality of life of patients with metastatic disease, when compared to no antitumour therapy [J. Clin. Oncol., 10(6), 904-11 (1992) and Br. Med. J., 306, 752-55 (1993)].
Insights into 5-FU molecular pharmacology have led to several strategies to modulate its cytotoxic effects. Infusional versus bolus administration of 5-FU resulted in a higher response rate (22% v. 14%) but did not significantly effect the median survival time (12.1 months v. 11.3 months). [Meta-analysis Group in Cancer. J Clin Oncol. 1988; 16:301-308.] The most successful approach has been the coadministration of 5-FU with folinic acid (FA), which increases the degree of inhibition of thymidylate synthase [G. J. Peters, C. L. van der Wilt, C. J. van Groeningen et al; Thymidylate synthase inhibition after administration of fluorouracil with or without Leucovorin in colon cancer patients: implications for treatment with fluorouracil; J. Clin Oncol, 12, no 10: 2035-2042 (1994)], depletes cellular thymidine, and induces apoptosis [C. Benz and E. Cadman; Modulation of 5-fluorouracil metabolism and cytotoxicity by antimetabolite pretreatment in human colorectal adenocarcinoma HCT-8; Cancer Res, 41, 994-999, (1981)]. Folinic acid has been approved in numerous European countries for the treatment of colorectal cancer. Among the various modulations and schedules of administration, high dose infusional regimens of 5-FU plus folinic acid (5-FU/FA) are widely used in Europe and have resulted in the highest response rates (up to 44%) and longest time to progression (around 7 months) and median survival (up to 16.6 months) over administration of bolus 5-FU/FA (J. Clin. Oncol, 15 (2), 808-815 (1997); J. Clin. Oncol, 16(2), 418-426 (1998); Ann of Oncol, 9, 727-731 (1998); Onkologie, 1 403-307 (1988).